The candidate's career plan is to become an academic cardiologist, combining his clinical and research interests in vascular biology and thrombosis. His commitment to a research career, established by two years at the NHLBI studying the biology of plasminogen activators, has been reinforced his clinical cardiology training and his first 2 years in the laboratory of Dr. Shaun Coughlin at UCSF. In the next 2-3 years he will acquire the additional technical and intellectual skills necessary to lay a broad and deep foundation for an independent research career as well as develop projects which he will continue to investigate in his own laboratory. Dr. Coughlin's laboratory (where he has been supported by a Howard Hughes Post-doctoral fellowship) is an especially attractive training environment for a physician scientist because of his experience with research fellows, his time commitment to the laboratory and his proven ability to address important questions in biology and medicine. The candidate will continue to take full advantage of the rich academic resources afforded by UCSF, which include numerous seminars, facility sponsored journal clubs, formal courses, meetings between laboratories investigating vascular and receptor biology as well as tremendous and accessible technical expertise. The research proposal focuses on the in vivo role of a new protease-activated receptor (PAR), called PAR2, and the search for new PARs in a genomic locus which they have characterized. Unlike PAR1, the thrombin receptor, PAR2's role in vivo is not known, although available evidence suggests important roles in endothelial, keratinocyte and gastrointestinal biology. Since no effective pharmacologic means of studying PAR2 are available, the most definitive method of addressing the hypothesis that PAR2 is important in the normal development and function of these systems is to disrupt the gene in mice using homologous recombination in embryonic stem cells. To assist in their analysis of PAR2 null mice they will also use gene targeting to knock the lacZ gene into the PAR2 locus, allowing them to follow receptor expression in vivo using the most sensitive and specific technique available. In addition, they will continue to investigate the PAR locus to search for additional thrombin receptors, revealed by the phenotype of our recent PAR1 knockout mouse, and other novel PARs. (End of Abstract)